The most common and characteristic physiological defect of Cystic Fibrosis (CF) is dysfunction of the CFTR C1-channel which blocks C1- transport. On the other hand, it is not widely appreciated that HCO3 ion-transport is also defective in most, if not all, organs affected in CF. In view of its critical role in setting pH and its known ability to exchange for C1-ions, abnormalities in HCO3 ion-management may be closely integrated with CF pathogenesis. The link between these two defects is not known, but the human sweat duct offers a unique opportunity to observe normal and defective C1-and HCO3 ion-transport in a native human tissue where the effects of CF markedly disturb electrolyte transport. Our data and other evidence indicates that HCO3 ion-is most probably transported via a C1-/HCO3 ion-anion exchange (AE) as it is in most other tissues. We propose to define AE function in sweat ducts from normal subjects and CF patients. We will characterize AE activity and HCO3 ion-transport in the plasma membranes of duct cells. Then, since electrochemical results show that not all C1- absorption in the duct can occur electroconductively through CFTR, we will determine whether AE activity accounts for the difference. Because phosphorylation state, ATP, and pH strongly influence CFTR activity and because C1-conductance and HCO3 ion-transport function together, we will determine whether any of these parameters regulate or influence HCO3 ion-transport also. Lastly, the severity of the HCO3 ion-transport defect appears to vary with distinct genotypes so we will use ducts from patients with known mutations in CFTR to determine if these mutations exert distinct effects on HCO3 ion-transport in the sweat duct. At present it is difficult to rationalize how a simple singular defect in C1-conductance can cause the myriad of abnormalities found in CF: namely, salty sweat, autolysis of the pancreas, atresia of the vas deferens, meconium ileus, depressed female fertility, and lung disease as well as a host of other abnormalities. Defining HCO3 ion-transport and its relevance to CFTR function should lend much to explaining, and hopefully, ameliorating these problems.